The present invention relates to a 3-substituted-phenyl-3-merthylbutyric acid and 3-substituted-phenyl-3-methylaldehyde derivatives, which are useful in the production of N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester, which is a sweetener with high sweetening potency.
In recent years, as eating habits have changed dramatically, excessive weight gain caused by the increasing amounts of sugar found in foods have resulted in health related problems. Accordingly, the development of a low-calorie sweetener (sweetening agent) that replaces sugar has been strongly in demand. An example of such a low-calorie sweetener that is commonly used is aspartame, which is safe and effective for providing a high level of sweetness. However, aspartame is somewhat unstable.
To solve these problems, an xe2x80x94[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester shown below has been found, which is not only highly stable but is also far better with respect to the sweetening potency it imparts. 
To make the N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester a process of reductively alkylating a xcex2-O-benzyl-xcex1-L-aspartyl-L-phenylalanine methyl ester with a 3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde followed by removing the benzyl group of a protecting group therefrom has been provided previously by the present inventors. However, in this process, the aldehyde, which is used as an intermediate in the process, requires 7 reaction steps to be synthesized from the 3-hydroxy-4-methoxy acetophenone, which is used as the starting material. This 7-step reaction scheme is shown in the Reaction Process 1 below. Therefore, from the point of industrial profitability, such a reaction is not desirable. 
In view of this problem, there is a need in the art for a process for producing industrially and easily the aspartyl dipeptide ester derivative described above.
Therefore, to solve this problem, the present inventors set out to provide processes for industrially and efficiently producing the N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester; and novel intermediate compounds useful in such production processes.
The present inventors have studied earnestly to solve the above problem, and as a result succeeded in newly synthesizing a 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde and found that the compound is extremely useful as an intermediate for the production of the N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester. Further, the inventors have discovered an efficient process for producing the compound, which is shown in the following reaction process 2. 
Therefore, an object of the present invention is to provide a process for producing compounds of formula (2): 
Another object of the present invention is produce 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid using the above compound of formula (2).
Another object of the present invention is to provide a process for producing 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde with the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid.
Another object of the present invention is to provide a process for producing N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester with the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde.
Another object of the present invention is a compound representated by formula (3): 
In the process for producing 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid, as depicted in the xe2x80x9cReaction Process 2xe2x80x9d shown below the following disclosure is provided: 
To protect the hydroxyl group in a 2-methoxy phenol, the 2-methoxy phenol can be converted to a hydroxyl-protective derivative of 2-methoxy phenol represented by formula (1) (where R is a sulfonyl-type protecting group and Me is a methyl group) by forming a sufonic acid ester from the 2-methoxy phenol, which process may be conducted as described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS (1991, JOHN WILEY and SONS. INC. NEW YORK), p.168-170, which is incorporated herein by reference. 
The reaction of 2-methoxy phenol with the corresponding sulfonic acid anhydride or sulfonic acid chloride can be performed in the presence of a base. An example of a hydroxyl protecting group can be represented by the formula: xe2x80x94SO2xe2x80x94Rxe2x80x2 as the sulfonyl type-protecting group. Rxe2x80x2 can be a branched chain or a straight chain (linear) alkyl group having 1 to 10 carbon atoms, which may have one or more substituent groups; an aryl group having 6 to 15 carbon atoms, which may have one or more substituent groups; and an aralkyl group having 7 to 20 carbon atoms, which may have one or more substituent groups. Preferably, the alkyl group(s) have from 1 to 3 carbon atoms. The alkyl group and/or the aralkyl group may be have a fluorine atom wherein one or more of the hydrogen atoms is replaced by fluorine atom(s). For example, a part or a whole of the alkyl group may be a fluoroalkyl group.
Examples of substituents on the alkyl and/or aralkyl include nitro group(s), halogen atom(s) (e.g, Cl, Br, F), and trialkyl ammonium group(s).
The R group, which is a sulfonyl type protecting group, may be, but not limited to, the following: a benzene sulfonyl group (xe2x80x94SO2xe2x80x94C6H5), a p-toluene sulfonyl group (xe2x80x94SO2xe2x80x94C6H4xe2x80x94CH3), a p-bromobenzene sulfonyl group (xe2x80x94SO2xe2x80x94C6H4xe2x80x94Br), a p-nitrobenzene sulfonyl group (xe2x80x94SO2xe2x80x94C6H4xe2x80x94NO2), a methane sulfonyl group (xe2x80x94SO2xe2x80x94CH3), an ammonioalkane sulfonyl group (xe2x80x94SO2xe2x80x94(CH2)nN(CH3)3+) (n=0 to 6), a trifluoromethane sulfonyl group (xe2x80x94SO2xe2x80x94CF3), a nonafluorobuthane sulfonyl group (xe2x80x94SO2xe2x80x94C4F9), a 2,2,2-trifluoroethane sulfonyl group (xe2x80x94SO2xe2x80x94CH2xe2x80x94CF3). Preferably, R is a methane sulfonyl group, a trifluoromethane sulfonyl group, or a p-toluene sulfonyl group.
The reaction of a hydroxyl-protective derivative of 2-methoxy phenol represented by formula (1) with a 3-methylcrotonic acid can be conducted without a solvent, or conducted in an organic solvent with an acid coexistent. The organic solvent can be any solvent which is inactive with the substrate, with an acid and with a reaction product in the reaction. Examples of such solvents include, methylene chloride, chloroform, and nitrobenzene.
When an acid is used, the acid to be used can be a proton acid (H+), such as sulfuric acid, para (p-)toluenesulfonic acid and hydrogen chloride, a Lewis acid (L.A.), such as aluminum chloride, and titanium tetrachloride. Plural acids can also be employed, respectively in the proton acid or Lewis acid. A proton acid can also be used in combination with a Lewis acid, such as combination of hydrogen chloride with aluminum chloride. In a preferred embodiment, the acid is fixed firmly onto the surface of a solid phase thereby simplifying the process. Preferred acids include, aluminum chloride, titanium tetrachloride and sulfuric acid.
The amount of acid to be employed is not limited particularly, however, an excess of acid relative to the 3-methylcrotonic acid, will allow the reaction to be completed in a shorter time. However, preferably the amount of acid relative to the 3-methylcrotonic acid is in an amount of not more than 5 molar equivalents, more preferably not more than 3 molar equivalents, and further more preferably from 0.1 to 3 molar equivalents.
The amount of the hydroxyl-protective derivative of 2-methoxy phenol represented by formula (1) relative to the 3-methylcrotonic acid is not limited, however, preferably at least 0.5 molar equivalents or more, more preferably 1 molar equivalents or more, and further more preferably 1 to 10 molar equivalents or so, is used relative to the 3-methylcrotonic acid.
There is no particular limitation on the reaction temperature, however, the higher the reaction temperature, the more secondary reactions occur; on the other hand, at a low temperature, the reaction speed becomes extremely slow. Therefore, a temperature of from about 20 to about 180xc2x0 C. is preferred, and more preferably a temperature of about 30 to about 100xc2x0 C.
To obtain a 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid by decomposing a sulfonic acid ester of 3-substituted-phenyl-3-methylbutyric acid represented formula (2), the reaction can be performed under basic conditions. The basic material to be employed is not particularly limited, but is preferably chosen from one or more of a metal hydroxide such as sodium hydroxide, and/or potassium hydroxide. The amount of basic material is also not limited but it is preferred that the basic material be included in an amount of about 1 molar equivalent or more (1 mole or more).
When a solvent is used in the reaction, any solvent can be used as described above. However, when a metal hydroxide such as sodium hydroxide, potassium hydroxide and the like is employed, the solvent(s) preferably also contains at least one of alcohols, such as methanol, ethanol and isopropyl alcohol; and water.
The reaction temperature for removing the protective sulfonic acid ester can be performed at any temperature. However, when a higher temperature is employed, the reaction can be completed in a shorter time. Preferably, a temperature of about 20 to about 150xc2x0 C., and more preferably about 40 to about 100xc2x0 C. may be used.
The aldehyde form of 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid can be produced by converting the carboxyl group in the carboxylic acid into a formyl group.
The 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid obtained in the above reaction may be directly reduced into the corresponding formyl group from the carboxyl group. Preferably, the reaction is performed as described in Chemistry Letters, issued in 1998, Nov., p.1143-1144 (which is incorporated herein by reference) whereby the starting material can be converted into the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde. This process involves reducing the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid with hydrogen in an organic solvent together with added pivalic acid anhydride, palladium acetate, and triphenylphosphine derivative.
In this reaction any organic solvent may be employed provided it is inactive with the starting material, a catalyst and a product in the reaction. Examples of solvents that can be used include acetone, tetrahydrofuran, and toluene.
The amount of pivalic acid anhydride to be used is at least an equimolar (equimole) quantity or more of pivalic acid anhydride relative to the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid; preferably, about 1 to about 5 times molar (moles) quantity of pivalic acid anhydride to the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid.
The triphenylphosphine derivative can be triphenylphosphine, tritolylphosphine, or similar derivatives. The palladium acetate and the triphenylphosphine derivative are employed as the catalyst, and therefore, only some mole % is needed.
The reaction can be performed at any temperature, preferably a temperature range of about 40 to about 100xc2x0 C., and more preferably a temperature of about 60 to about 80xc2x0 C. At the higher temperatures, the reaction may be promoted, and can be finished (completed) in a shorter time.
In other embodied methods of forming a 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde, the 3-substituted-phenyl-3-methylbutyric acid represented by formula (2) the following two processes are described.
Process 1:
As shown in the following reaction scheme, the carboxyl group in the 3-substituted-phenyl-3-methylbutyric acid represented by formula (2) is completely reduced to a hydroxymethyl group, and then the hydroxymethyl group is partially oxidized to form a formyl group. In this case, the reductionxe2x80x94partial oxidation reaction can be conducted as described in the Journal of Organic Chemistry, vol. 48, No. 25, p. 5043-5048, 1983, which is incorporated by reference.
The sulfonic acid ester is deprotected; and then the acetyl, such as a dimethyl acetal group, protecting the formyl group is removed through acidic hydrolysis, whereby the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde can be obtained. 
Process 2:
As shown in the following reaction route, the carboxyl group in the 3-substituted-phenyl-3-methylbutyric acid represented by the general formula (2) can be reduced from the carboxyl group to the formyl group, and the formyl group can be protected with an acetal group, such as dimethyl acetal group, and then the sulfonic acid ester is decomposed, and subsequently, the acetal group is removed through acidic hydrolysis whereby the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde can be obtained. 
Between these two processes, reaction process 2 is preferred.
Production of N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester from the 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl aldehyde can be achieved by reductively alklyating the aldehyde with an xcex1-L-aspartyl-L-phenylalanine methyl ester (aspartame) under a hydrogenation condition (hydrogen addition) to yield the aspartyl dipeptide ester derivative.
In such a reaction, any solvent can be used provided it is inactive with the starting material, a catalyst and a product in the reaction. A homogeneous organic solvent which can dissolve the aspartame and the above described aldehyde, and which is a single solvent of one kind of organic solvent only; a mixture of organic solvents; or a mixed solvent with water may be used.
Examples of such organic solvents include, but not limited to, alcohols, such as methanol, and ethanol, tetrahydrofuran, acetonitrile, and dimethylformamide. From a practical standpoint, alcohol(s) such as methanol or water-containing alcohol(s), such as water-containing methanol are preferred.
If a catalyst is used for hydrogenation (hydrogen addition), then such catalysts can be chosen from, for example, palladium based catalyst, platinum based catalyst, and rhodium based catalyst.
The reductive alkylation reaction can be conducted through hydrogenation (hydrogen addition), and under hydrogen pressure, preferably from about 0.1 to about 1.0 MPa.
The reaction temperature can be chosen so that the reductive alkylation proceeds suitably, for example, to suppress (limit) a secondary reaction and to promote the reaction desired, a temperature range of about 15 to about 50xc2x0 C. for about 2 to about 72 hours can be used.
The molar ratio of aspartame to the starting aldehyde can be from about 0.5 to about 1.5 moles of the aspartame per 1 mole of the aldehyde.
The Friedel-Crafts reaction, which uses a hydroxyl-protective derivative of 2-methoxy phenol represented by formula (1) is known and described in the Journal of the Agricultural Food Chemistry (1997), vol. 45, No. 6, page 2047-2054. Therefore, according to this known process, as shown in the reaction process 3 below, a phthalic anhydride and a 2-methane sulfonyloxy anisole are subjected to a Friedel-Crafts reaction in the presence of aluminum chloride yielding methane sulfonic acid ester, which in turn is hydrolyzed to obtain a 2-(3-hydroxy-4-methoxybenzoyl)benzoic acid.
In this process, it is possible to introduce an acyl group at the para-position to a methoxy group located on the benzene ring, but the yields are low. Accordingly, it is difficult to estimate the yield obtained in the Friedel-Crafts reaction with a 3-methylcrotonic acid and particularly, whether it proceeds to obtain high yields of the target product. However, in this known reaction the butyric acid derivative, which is extremely useful as an intermediate for producing the sweeteners described herein, were not suggested. 
A similar process, as described in International Patent Publication W099/18064, provides that a compound having a benzene ring with an electron donating group (electron releasing group) at the ortho-position to a phenolic hydroxyl group located on the benzene ring, the phenolic hydroxyl group is protected by a sulfonic acid ester, and then an electrophilic reagent is reacted with the ester, whereby the reaction proceeds at the para-position to the electron donating group on the benzene ring. However, in the Friedel-Crafts reaction described in WO99/18064, substances such as acid chloride, acid anhydride, 3-chloro-2-methylpropene, and the like, which are all known are reacted in the presence of an acid.
On the other hand, it is difficult to say that a process using a 3-methylcrotonic acid as an electrophilic reagent in the Friedel-Crafts reaction was not well-established. For example, in a process for reacting an anisole with a 3-methylcrotonic acid in the presence of aluminum chloride (as in the present invention) to synthesize a 3-(4-methoxyphenyl)-3-methylbutyric acid, (which is described in the Journal of Organic Chemistry (1972), vol. 37, No. 36, p. 825-836), the 3-(4-methoxyphenyl)-3-methylbutyric acid obtained gives a yield of about 10% to the 3-methylcrotonic acid employed, and therefore this process is not particularly useful with respect to the yield. Therefore, it was quite surprising that the crotonic acid derivative as found in the present invention, can be used to produce the objective derivative at an extremely high yield. In the same manner as above, from the above described known process, the butyric acid derivative obtained in the present invention, which is extremely useful as an intermediate for producing the sweeteners described herein, was not suggested. 